Acetals and ketals of 9-fluoro-12-oxygenated-16, 17, 21-trihydroxy steroids of the pregnane series and intermediates therefor



3,093,631 Patented June 11, 1963 ice This invention relates to the synthesis of new steroids and, more particularly, has for its objects the provision of: (I) advantageous processes for preparing 9uz-fiuor0- 12,16a,l7a,2l-oxygenated progesterones and l-dehydroprogesterones; and (II) certain steroids useful themselves as physiologically active steroids or in the preparation of physiologically active steroid derivatives.

The processes of this invention can be summarized by the following equations:

wherein the 1,2-position is saturated or double-bonded;

R is hydrogen or an acyl radical [preferably the acyl radical of a hydrocarbon carboxylic acid of less than ten carbon atoms as exemplified by the lower alkanoic acids (e.g., acetic, propionic, hutyric and enanthic acid), the monocyclic hydrocarbon aromatic carboxylic acids (e.g., benzoic acid), the monocyclic hydrocarbon andkanoic acids (e.g., phenacetic and ,B-phenylpropionic acid), the lower alkenoic acids, the cycloalkanecarboxylic acids and the cycloalkenecarboxylic acids], P is hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl, halo lower alkyl, carboxy lower alkyl (or a salt or ester thereof), monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; or together with the carbon to which they are joined P and Q is cycloalkyl or monocyclic heterocyclic. Particularly preferred are those compounds wherein R is lower a1- kanoyl; P is hydrogen or lower alkyl; and Q is lower alkyl or monocyclic aryl.

To prepare the compounds of this invention in accordance with one process of this invention, 1119,125- epoxy-A -pregnadiene-Z1-oI-3,20-dione (or a ZI-ester thereof, preferably a 21-ester with a hydrocarbon carboxylic acid of less than ten carbon atoms, such as one of the esters enumerated hereinbefore) is treated with hydrogen fluoride whereby a mixture of 12m-fiuoro-A pregnadiene-l 1,8,2 l-diol-3,2 lione and 9a-fluoro-A pregnadiene-IZm,2l-diol-3,20-dione (or the corresponding 21-esters thereof) is obtained. This mixture is then separated chromatographically to yield the new intermediates of this invention, namely, 9a-fluoro-A -pregnadiene-l2;3,2l-diol-3,20-dione (and Zl-estcrs thereof), Compounds A. 'lhe reaction is preferably conducted in an organic solvent for the steroid reactant in the cold (e.g., at a temperature of 0 C. or below).

If desired, the 9a-fiuoro-A -pregnadiene-12fl,2l-diol- 3,20-dione (or 2l-ester thereof) can then be treated with 2,3-dichloro-5,6dicyanohydroquinone to yield the corresponding 9a-fiuoro-A -pregnatriene-l2fl,2l-diol-3,20- dione (or 21-e-ster thereof). The reaction is preferably conducted by dissolving the steroid in an organic solvent and carrying out the reaction at the reflux temperature of the solvent.

Compounds A are then treated with osmium tetroxide, preferably in the presence of an organic base, such as pyridine, to yield the osmate ester of corresponding 16m- 17a-dihydroxy derivative, which is then hydrolyzed, as by treatment with sodium sulfite or hydrogen sulfite, to yield the free ladh-dihydroxy intermediates of this invention (Compounds B).

Compounds 13 are then treated with an aldehyde or ketone of the general formula:

wherein P and Q are as hereinbefore defined to yield certain final products of this invention (Compounds C). The reaction is preferably carried out by treating a suspension or solution of the steroid in the aldehyde or ketone (or an organic solvent if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluene sulfonic acid and hydrochloric acid), neutralzizing the acid and recovering the cyclic acetal or ketal derivative.

Among the suitable aldehyde and ketone reactants are included all aldehydes of at least two carbon atoms and all ketones. These include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal, and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclob-utanone, cyclopentanone, cyclohexanone, suberone, and cyclodexanone; mono and dicycloalkyl ketones, such as cyclohexylmethylketone and dicyclopropylketone, halo-lower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafluorobutanol ethyl hemiacetal; halolower alkanones, such as 1,1,l-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower 'alkoxybenzaldehydes (e.g. o anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hy-droxybenzaldehydes (e.g. salicylaldehyde), dihydroxybenzaldehydes (e.g. resorcyaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and pethylbenzaldehyde), di(lower alkyl)benzaldehydes (e g. o,p-dirnethylbenzaldehyde), nitrobenzaldehydes, acylamidobenzaldehydes (e.g. N-acetylanthranilaldehyde), and cyanohenzaldehydes; monocyclic carbocyclic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, B-phenylpropionaldehyde, y-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives thereof; mono-cyclic heterocyclic lower alkanals; l-(monocyclic carbocyclic aromatic) substituted lower alkanols, such as acetophenone, a,a,a-tlifil.l01'0aCetO- phenone, propiophenone, butyrophenone, valerophenone, isocaprophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone), (lower alkoxy)phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketones, hydroxyphenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone), (lower alkyl) phenyl lower alkyl ketones (e.g. methyl p-tlyl ketone), di(lower alkyl)phenyl lower alkyl ketones (o,p-xylyl methyl ketone), nitrophenyl lower alkyl ketones (e.g. pnitroacetophenone), acylamidophenyl lower alkyl ketones (e.g. acetyl anilines), and cyanophenyl lower alkyl ketones; benzophenone, and mono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as l-p-henyl-S-butanone and 1-phenyl-4-pentanone, and aromatically substituted derivatives thereof; l-(monocyclic heterocyclic)-substituted lower alkanals, such as Z-acetylfuran, Z-benzoyl-furan, and Z-acetylthiophene; oxo substituted monocyclic heterocyclics, such as alloxan; monocyclic heterocyclic lower alkanones; and oxo lower alkanoic acids such as glyoxylic pyruvic, acetoacetic, fl-ketopropionic, a-ketobutyric, levulinic, fi-ketocaproic and fi-ketocaprylic acid [as well as salts and esters thereof, such as the lower alkyl esters (e.g. methyl and ethyl) Alternatively, Compounds C can be prepared by reacting the starting steroids, namely, the 115,1213-epoxy- A -pregnadiene-21-ol-3,20-dione and its 21-esters, with osmium tetroxide under the conditions detailed hereinbefore to yield the new I118,1ZB-epoxy-M-pregnene-16a, 17a,2l-triol-3,20-dione and its Zl-esters of this invention (Compounds D), which can, if desired, be l-dehydrogenated with chloranil as described hereinbefore, to yield the corresponding A -pregnadiene derivatives.

Compounds D are then treated with an aldehyde or ketone of the general formula:

preferably one of the aldehydes or ketones listed hereinbefore, to yield the corresponding 16,l7cyclic acetal or ketal derivative (Compounds E), which in turn are then treated with hydrogen fluoride to yield Compounds C.

If desired, Compounds C can then be oxidized, as by treatment with chromic oxide to yield the corresponding 12-keto derivatives (Compound-s F). Moreover, if Compounds C and/or F are initially obtained in the form of their free 2l-hydroxyl form, they can be converted to ester derivatives by treatment with the acyl chloride or acid anhydride of the desired acid, preferably one of the acids listed hereinbefore, the reaction preferably being conducted in the presence of an organic base, such as pyridine.

The final products of this invention can be represented by the general formula CHzOR wherein the 1,2-positio-n is saturated or double-bonded, R is hydrogen, R" is fi-hydroxy, or together R and R" is keto, and R, P and Q are as hereinbefore defined.

The final products of this invention are physiologically active substances which possess glucocorticoid activity and hence can be used in lieu of known glucocorticoids, such as hydrocortisone, in the treatment of rheumatoid arthritis, for example.

In addition to their physiological use, Compounds F are also useful as intermediates in the preparation of corresponding 9(ll)-dehydro derivatives (Compounds G) to which they are converted by treatment with a strong base, such as sodium hydroxide. These 9(11)-dehydro derivatives are physiologically active substances which possess glucocorticoid activity and hence can be used in lieu of known glucocorticoids, such as hydrocortisone in the treatment of rheumatoid arthritis, for example.

The following examples illustrate the invention, all temperatures being in Centigrade:

EXAMPLE 1 9ut-F l aura-A -Pregnadi en e-] 2 fl,2 I -Di0I-3,20-Dione 21 -A cetate (a) Preparation of I1[3,12[i-oxidodcsoxycorticoster 0ne.Surface growth from each of 2 three-week old agar slant cultures of Wojnowicz'a graminis NRRL 2472, the slant containing as a nutrient medium (A): glucose, 10 g.; Difco yeast extract, 2.5; K HPO l g.; agar, 20 g.; and distilled water to l 1., are suspended in 2.5 ml. of an 0.01% sodium lauryl sulfate aqueous solution. One milliliter portions of the suspension are used to inoculate four 250 ml. conical flasks, each containing ml. of the following sterilized nutrient medium (B): dextrose, 10 g.; cornsteep liquor, 6 g.; NH I-I PO 3 g.; Difco yeast extract, 2.5 g.; CaCl 2.5; and distilled water to l 1. After 4 days of incubation at 25 C. with continuous rotary agitation (280 cycles per minute, 2 inch radius), 10% (VOL/vol.) transfers are made to twenty 250 ml. conical flasks each containing 50 ml. of fresh sterilized medium B. After an additional incubation period of three days, 10% transfers from these flasks are made to two hundred 250 ml. conical flasks each containing 50 ml. of fresh sterilized medium B. llfigllfl-oxido progesterone is added by adding to each flask 0.25 ml. of a sterile solution of the steroid in N,N-dimetl1ylformamide (6O mg./ml.) so that the medium is supplemented with 300 g/ ml. of steroid. After 48 hours of further incubation, the contents of the flasks are pooled and filtered through a Seitz clarifying pad. The flasks, mycelium and pad are washed with successive 50 ml. portions of warm water. The combined filtrate and washings have 21 volume of eleven liters. This is extracted with three 3.3 1. portions of chloroform which are combined, washed twice with 5 1. portions of water and evaporated to dryness in vacuo. The residue (2.3 g.) on crystallization from acetone-hexane gives 1.0 g. of 1lfi,12B-oxidodesoxycorticosterone.

(b) Preparation of 1I 8,IZB-oxido-M-pregnene-I8on2]- dial-3,20-dione.Streptmyces roseochromogenes (Waksman No. 3689, The Institute of Microbiology, Rutgers University, New Brunswick, New Jersey) culture is maintained on Gould agar (agar, 20 g.; glucose, 10 g.; yeast extract, 2.5 g.; K HPO l g.; distilled water to 1 liter). Inoculum for the first flask stage is prepared by suspending the surface growth from a two-week old agar slant culture with 5 ml. of an 0.01% Dupanol solution. One milliliter portions of inoculum are used to inoculate ten 250 ml. Erlenmeyer flasks, each containing 50 ml. of the following medium (A):

Grams Soybean meal 20 Glucose 30 Soybean oil 2.2 Calcium carbonate 2.5

Distilled water to 1 liter.

The flasks are then incubated at 25 on a rotary shaker 280 cycles/minute, 2 inch radius) for 72 hours. After 72 hours, a transfer (by volume) is made to each of 47 250 ml. Erlenmeyer flasks, each containing 50 ml. of the same medium A. At the time of inoculation of these flasks, 25 mg. of steroid is added to each flask using 0.25 ml. per flask of a 100 mg./ml. solution of 11fl,l25-oxidodesoxyoorticosterone in N,N-dimethylformarnide. A total of 1.09 g. of steroid is thereby fermented. After inoculation and supplementation the flasks are then incubated undcr the same conditions as described above. At approximately 70 hours after steroid addition, the culture broths are harvested. The contents from each flask are pooled and the pooled broth is then adjusted to pH 4.5 using 12 N H 80 The acidified broth is then filtered through a Buchner-Seitz clarifying pad apparatus. The filtrate (3000 ml.) is collected and extracted three times with one liter portions of chloroform. The combined chloroform extracts are washed twice with 1.5 l. of water and then evaporated to dryness in vacuo. Crystallization of the residue from acetone-hexane give about 300 mg. of l1,8,12,8-oxido-A -pregnene-16a,2l diol-3,20-dione.

(c) Prepamrion of 11,8,I25-oxid0-21-chloro-A -pregnadiene-3,20-di0ne.-To a cold solution of 240 mg. of 11,8,l2fi-oxido-A -pregnene-16a,21-diol-3,20dione in 15 ml. of dry pyridine, 0.6 ml. of methauesulfonyl chloride is added dropwise. The reaction mixture is stoppered and kept at 5 for 2 hours following which crushed ice is added to decompose the excess methanesulfonyl chloride. The mixture is then distributed between chloroform and water. The chloroform is separated, washed successively with 2 N HCl, 5% NaHCO and water and evaporated to dryness in vacuo. The residue is chromatographed on 6 g. of Florisil. Elution with benzene, evaporation of the solvent in vacuo and crystallization from acetone-hexane gives 100 mg. of l1,6,l2fl-oxido-2l-chloro-n -pregnadiene-3,20-dione.

(d) Preparation of 1I5,1Zfi-oxido-M -pregizadiene-Zl-' ol-3,20-di0ne 21-acetate.-T0 a solution of 699 mg. of 1 1,8,lZB-oxido-Z1-chloro A -pregnadiene-3,ZO-dione in 150 ml. of acetone containing 0.075 ml. of acetic acid, 640 mg. each of potassium iodide and freshly fused potassium acetate are added. The mixture is protected from moisture and refluxed on a steam bath for 16 hours. After cooling the mixture is filtered and washed well with acetone. The filtrate is diluted with 150 ml. of water and on concentration of the solution in vacuo crystals separate which are filtered, washed with water and dried to give 638 mg. of l113,l2e-oxido-A -pregnadiene-2l-ol- 3,20-dione 2l-acetate.

(2) Preparation of 9a-flu0r0-. -pregnadicne-I213,21- dial-3,20-di0ne 21-acemte.-To a stirred solution of 64.4

mg. of 115,12,8-oxido-A -pregnadiene-Zl-ol-3,20-dione ZI-acetate in 5 ml. of chloroform and 1.2 mg. of tetrahydrofuran contained in a polyethylene bottle and cooled by means of an acetone-Dry Ice bath, 1.0 ml. of hydrogen fluoride is pipetted by means of a polyethylene pipette. The reaction vessel is stoppered and left at 5 C. for 5 hours and then poured into a polyethylene beaker containing 50 ml. each of chloroform and ice water. The mixture is neutralized with sodium bicarbonate, the chloroform separated, washed with water and evaporated to dryness in vacuo. The residue is chromatographed on Woelm neutral alumina. Elution with 10% chloroform in benzene yields first 9a-fluoro-A -pregnadiene-125,21- diol-3,20-dione 21 acetate, which on crystallization from acetone-hexane yields a pure product which melts at about 215-217; [11, +1 l2 (chlf.);

Mg; 238 my (e=28,500); A35? 292, 5.71, 6.02, 6.19, 6.30;.

Ar1aIysis.-Calcd. for C H O F (404.46): C, 68.29; H, 7.22. Found: C, 68.42; H, 7.03,

and subsequently lZe-fluoroM -pregnadiene-115,21-diol-3,20-dione 2l-acetate.

EXAMPLE 2 9e-Flw0r0-A -Pregnatriene-1213,21 -Di0l-3,20-D ione 21 -A cetate To a solution of 1.0 g. of 9e-fluoro-A "-pregnadienel2j3,2l-diol-3,20-dione ZI-acetate in 50 ml. of purified dioxane 700 mg. of 2,3-dichloro-5,6-dicyanobenzoquinone are added and the resulting solution refluxed under nitrogen for six hours. After cooling the precipitate-d 2,3-dichloro-5,o-dicyanohydroquinone is filtered and Washed with dioxane. The combined filtrate and washings are diluted with an equal volume of chloroform and adsorbed onto 40 g. of Woelm neutral alumina. Elution with chloroform and crystallization of the residue of the eluates from acetone-hexane gives 9a-fluoro-A pregnatriene-12,6,2l-diol-3,20 dione ZI-acetate.

EXAMPLE 3 9a-F luoro-M- -Pregnadiene-l 219,21 -Diol-3,20-D ionc To a solution of 25 mg. of 9a-fiuoro-A -pregnadienel2B,21-diol-3,20-di0ne ZI-acetate in 5 ml. of methanol (oxygen free) is added 0.5 ml. of 10% aqueous potassium carbonate and the solution left under nitrogen for 2 hours. The solution is then neutralized with acetic acid diluted with 3 ml. of water and evaporated in vacuo whereupon the 9a-fluoro-A -pregnadiene-12,8,21-diol-3, 20-dione crystallizes and is filtered, washed with water and dried.

EXAMPLE 4 9a-F lnoro-A -Pregnatri en e-I 2,8,2] -Diol-3,20-Dione Following the procedure of Example 3 but substituting 9e-fluoro-A -pregnatriene-11 8,21-diol 3,20 dione 21- acetate for 9a-fluoro-A -pregnadiene-12p,2l-diol-3,20- dione 21-acetate there is obtained 9a-fiuoro-A -pregnatriene-12p,21-dio1-3,20-dione.

EXAMPLE 5 9a-Fluor0-A -Pregn en e-] 213, I 6 0:,1 7a,21 -Tetr0l-3,20- Dione 21 -A cetate To a stirred solution of 101 mg. (0.25 mmol) of 9afiuoro-A -pregnadiemd2,8,2l-diol-3,20-dione ZI-acetate in 10 ml. of benzene containing 0.3 ml. of pyridine, a solution of 64.5 mg. (0.25 mmol) of osmium tetroxide in 1 ml. of benzene is added dropwise over a 10 minute period. The solution is stirred at room temperature for 20 hours and then 10 ml. of an oxygen-free solution con taining 800 mg. each of sodium sulfite and potassium bicarbonate is added followed by 5 ml. of oxygen-free methanol. The mixture is stirred under nitrogen for 5 hours, then filtered, and washed well with chloroform and tetrahydrofuran. The filtrate is washed with water and evaporated to dryness, in vacuo. Crystallization of the residue from acetone-hexane gives about 30 mg. of 9a-fluoro-A -pregnene-125,16a,17a,21-tetrol-3,20dione ZI-acetate having M.P. about 225-226;

Analysis.Calcd. for C H O F (438.48): C, 62.99; H, 7.13. Found: C, 62.80; H, 7.47.

EXAMPLE 6 9oc-Flu0r0-A -Pregnadiene-125J6a,I 701,21 -Tetrl- 3,20-Di0ne ZI-Acetate EXAMPLE 7 9a-Flu0r0-A -Pre gnene-I2B,16a,1 7 01,21 -Tetr0l-3 ,20- Diane 16,1 7-A cetom'de 21 -Acetate A solution of 30.7 mg. of 9wfluoro-A -pregnene-125, 16a,l7a,2l-tetrol-3,20-dione 21-acetate in 10 ml. of acc tone containing 0.01 ml. of perchloric acid is left at room temperature for 2 hours. It is then neutralized with NaHCO and diluted with ml. of water. Slow evaporation of the acetone in vacuo yields the crystalline 9a-fluoro-A -pregnene-12p,16a,17a,21-tetrol-3,20-dione 16, 17-acetonide ZI-acetate which is filtered, washed with water and dried. M.P. about 278-280"; [a] +78 (chlf.);

Am, 237 m (e=l9,500); Ami? 2.80, 5.70, 5.79, 5.96, 6.14;;

Analysis.-Calcd. for C15H35017F (478.54): C, 65.26; H, 7.37; F, 4.05. Found: C, 65.88; H, 7.16; F, 4.00.

EXAMPLE 8 9a-Flu0r0-A -Pregnene-12B,]6a,17a,21-Tetr0l-3,20- Dione 16,17-Acet0phenonide ZI-Acetate Following the procedure of Example 7 but substituting an equivalent amount of acetophenone for the acetone, 9a-fluoro-A -pregnene-12p,16a,17a,21-tetrol3,20-dione 16,

l7-acetophenonide 2l-acetate is obtained.

Similarly, substitution of any of the other aldchydes or ketones listed hereinbefore for the acetone in the procedure of Example 7 results in the preparation of the corresponding 16,17-acetal or ketal derivatives.

EXAMPLE 9 9u-Fluoro-A -Pregnadiene-12;3,I6a,17u,21 -Tetr0l- 3,20-Dione 16,17-Acetonide 21-A cetate Following the procedure of Example 7 but substituting an equivalent amount of 9a-fiuoro-A -pregnadiene-126, 1612-17a,21-tetrol-3,20-dione ZI-acetate for the Qua-fluoro- A -pregnene-12fi,16a,l7a,2l-tetrol-3,20-dione 2l-acetate, Qa-fluoro-A -pregnadiene-12B,16a,17a,21-tetrol 3,20-dione 16,17-acetonide 2l-acetate is obtained.

Similarly, 9a-fluoro-A -pregnene-12p,16u,17a,2l-tetrol- 3,20-dione and Qu-fluoro-A -pregnadiene-12B,l6u,17a, 21-tetr0l-3,20-di0ne yield their respective 16,17-acetonides when treated by the process of Example 7.

8 EXAMPLE 10 Ninety-eight milligrams of 1l 8,IZB-OXido-M -pregnadiene-21-ol-3,20-dione ZI-acetate is treated with 69 mg. of osmium tetroxide as described in Example 5 and gives on crystallization from acetone-hexane about 35 mg. of 11,8,l2B-oxido-A -pregnene-16m,17a,21-triol-3,20-dione 21- acetate having M.P. about 228-230"; [04 +166 (chlfi);

Age, 239 m 15:17,.300 my 2.85, 2.94, 5.72, 5.81, 6.07, 6.21,.

AnaIysis.Calcd. for C H O (418.47): C, 66.00; H, 7.22. Found: C, 66.58; H, 7.54.

EXAMPLE 1 1 116,126 Oxido A Pregnadiene 16a,17a,21 Trial- 3,20-Di0ne 21-Acetate Following the procedure of Example 2 but substituting an equivalent amount of 1l6,l2B-oxido-A -pregnene-16a,- 17a,2l-triol-3,20-dione ZI-aoetate for the 9oz-fltl0TO-A pregnadiene-l2;3,2l-diol-3,20-dione 2l-acetate, 1113,1213- oxido-a pregnadiene-l6a,17a,21-tri0l-3,20-dione 21-acetate is obtained.

EXAMPLE 12 116,125 Oxr'do A Pregnene 16a,17a,21 Triol 3,20- Dione Following the procedure of Example 3 but substituting an equivalent amount of 11,8,l2fl-oxido-A -pregnene-l6a,- l7a-2l-triol-3,20-dione 21 acetate for the 9afiuoro-A pregnadiene-l2fl,2l-diol-3,20-dione 21-aoetate, 115,121?- oxido-A -pregnene-16a,17a,21-triol-3,20dione is obtained.

EXAMPLE 13 115,12}?! Oxido A Pregnadiene 16a,17a,21 Triol- 3,20-Dione Following the procedure of Example 3 but substituting an equivalent amount of 115,12fl-oxido-A -pregnadiene- 16a,17a,21-triol-3,20-dione ZI-aoetate for the 9a-fluoro- A -pregnadiene-12fi,21-di0l-3,20-dione 2l-acetate, 116,- 12 3 oxido A pregnadiene 16cz,l7oc,21 triol 3,20- dione is obtained.

EXAMPLE 14 115,123 Oxido A Pregnene 16a,17a,21 -Triol 3,20- Dz'one 16,17-Aceronide 21-Acetate Twenty-one milligrams of 113,12fl-oxido-M-pregnene- 16a,17u,21-triol-3,20-dione 21-aoetate is treated with 5 ml. of acetone containing 0.005 ml. of perchloric acid as described in Example 7 and gives about 18.4 mg. of 1113,- 12fl-oxido-Aflpregnene- 1 60, 17 (1,2 1 -triol-3,20-dione 16,17- aoetonide 21-acetate having M.P. about 240-242; [a] +l chlf.);

A513, 239 mu (e=17,500); 1234'? 5.70, 5.78, 5.99, 6.19 1.

Analysis.-Calcd. for C26H34O7 (458.53): C, 68.10; H, 7.47. Found: C, 68.15; H, 7.51.

EXAMPLE 15 115,126 Oxido A Pregnene 161x,17u,21 TriOl 3,20- Dione 16,17-Acetophen0nide 21 -Acetate Following the procedure of Example 14 but substituting an equivalent amount of acetophenone for the acetone, 1 1,8,12fl-oxido-A -pregnene-16u,17,21-triol-3,20-dione 16,17#acetophenonide ZI-aoetate is obtained.

Similarly, substitution of any of the other aldehydes or ketones listed hereinbefore for the acetone in the procedure of Example 14 results in the preparation of the corresponding 16,17-acetal or ketal derivatives.

9 EXAMPLE 16 1118.12 Oxido-A Pregnadiene 16a,17a,21 Trial- 3,20-Dione 16,17-Acetonide 21 -Acetate EXAMPLE 17 9a Fluoro A Pregnene 12B,16n,17u,21 Terrel- 3,20-Dine 16,17-Acetonide 21 -Acetate A solution of 15 mg. of 11,3,l2fi-oxido-M-pregnene- 16a,17a,21-triol-3,20-dione 16,17-aoetonide 2l-acetate in ml. of chloroform and 1.2 ml. of tetrahydrofuran con tained in a polyethylene bottle is cooled in an acetone-Dry Ice bath and 1.0 ml. of hydrogen fluoride is added. The bottle is stoppers-d and left at 0 for 6 hours and then poured into a mixture of 50 ml. each of ice water and chloroform contained in a polyethylene beaker. The mixture is neutralized with sodium bicarbonate, the chloroform separated, washed with water and evaporated to dryness. Chromatography of the residue on alumina gives on crystallization from acetone-hexane 9u-fiuoro-N-pregnone-12p, l6:1,17a,2l-tetrol-3,2-0-dione 16,17-acetonide 21- acetate.

EXAMPLE 18 9a Fluoro A Pregnadiene I2fl,16a,17a,21 Tetra!- 3,20Di0ne 16,17-Acetonide 21-Acetate Following the procedure of Example 17 but substituting an equivalent amount of l1B,l2fi-oxido-a -pregnadiene 16a,17e,21-triol-3,20-dione 16,17-acetonide ZI-acetate for the l1B,12,6-oxido-A -pregnene-16a,17a,21-triol-3,20- dione 16,17 -acetonide 21-acetate, 9n-flu-oro-A -pregnw diene-IZB,16a,17a,21 tetrol-3,20-dione 16,17-acetonide 21- acetate is obtained.

Similarly, I 1 9, IZB-oXido-M-pregnene-I 6a,17 11,2 l-triol- 3,20-dione 16,17-acetophenonide 21-aoetate, 115,12B-oxido-A -pregriene-16a, 170:,21-111'01-3 ,20-dionc 16,17-aoetohide and l1p,12,8-oxido-A regnadiene-IGaJ7a,2l-triol- 3,20-dione 16,17-acetonide yield 9a-fluor'o-A -pregnene- 12,6, 160:, 170:,2 l-tetrol-SJO-dione 16,17-aoetophen0nide 21- acetate, 9a-fluoro-A -p-regnene-12fl, 16a, 1 711,2 1-tetrol-3 .20- dione 16,l7-acetonide and 9a-fluoro-A -pregnadiene 1219,- 1611,17 a,21itI'0]-3,20-di0116 16,17 -aoetonide, respectively.

EXAMPLE 19 9a Fluoro A Pregnene 160:,170z,21 Trial 3.12.20 Trione 16,17-Acet0nide 21 -Acetate A solution of 6.3 mg. of 9a-fluoroA -pregnene-12fl; 16a,17a,21-tetrol-3,20-dione 16,17-aoetonide ill-acetate in 1 ml. of reagent grade acetone is treated with 0.03 ml. of a solution of chromic anhydride and sulfuric acid in water (Jones reagent). After minutes the excess oxidizing agent is decomposed with methanol and the mixture diluted with water and extracted with chloroform. The chloroform is washed with water and evaporated to dryness, in vacuo. Crystallization of the residue from acetone-hexane gives 9a-fiuoro-A -pregnene-16a,l7u,2l-triol- 3,12,20-trione 16,17-acetonide ZI-acetate having MP. about 219220.;

A21 235 mu (e=18,000); REE 5.70, 5.78, 6.00, 6.15;;

EXAMPLE 20 9a Fluoro A Pregnadiene 16a,17a,21 Trial 3 12,20-Tri0ne 16,]7-Acetoniae 21-Acetate Following the procedure of Example 19 but substituting 10 an equivalent amount of 9u-fluoro-A -pregnadiene12.5,- lou,l7u-2l-tetrol-3,20-dione 16,17-acetonide ZI-acetate for the 9a-fiuoro-A -pregnene-123,1641,l7u,2l-tetrol-3,20- dione 16,17-aoetonide ZI-acetate, 9u-flu-oro-A -pregnadiene-l 6m,l7a,2l-triol-3,12,20-trione 16,17-acetonide 21- acetate is obtained.

Similarly, 9a-fluoro-A -pregnene- 125,1 6u,17a,2l-betr0l- 3,20-dione 16,17-acetophenonide 21-acetate, 9a-fluoro-A pregame-12,8, 16a, 17,2 l-tetrol-3,20dione 16,17-aoetonide and 9m-fluoroeA -pregnadiene-1'2p,16e,l7u,2l-tetrol- 3,20-dione 16,17-aoetonide yield 9a-fluoro-A -pregnene 16a,17a,21-trioI-3,12,20-trione 16,17-acetophenonide 21- acetate, 9afiuoro-A -pregnene l6a,l7e,2l Biol-3,12,20-

trione 16,17-acetonide, and 9u-flu-oro-A -pregnadienel6m,l7a,2l-triol 3,12,20-trione 16,17-aoetonide, respectively.

EXAMPLE 21 A -Pregnadiene-16a,1 70:,21-triol-3,12,20-Tri0ne I 6,] 7-A cetonide 21 -A cemte To a solution of 9a-fluoro-A -pregnene-l6u,1741,21- triol-3,l2,20-trione 16,17-acetonide Zl-acetate in tetrahydrofuran a dilute solution of sodium hydroxide is added. After 30 minutes at room temperature under nitrogen the solution is neturalized, diluted with water and extracted with chloroform. Evaporation of the chloroform and acetylation of the residue with acetic anhydride and pyridine gives n -pregnadiene-lfiu,l7a,2l-triol-3,l2, ZO-trione 16,17-acetonide ZI-aeetate.

EXAMPLE 22 M- -Pregnadiene-16a,17a,21-Triol-3,12,20-Tri0ne 16,1 7 -A cetophenonide Following the procedure of Example 21 but substituting an equivalent amount of 9a-fluoro-A -pregnene- :,170:,21-121i0l-3,12,20-lri01'l6 16,17-acetophenonide 21- acetate for the acetonide, A -pregnadiene-Ma,17a, 2l-triol-3,l2,20trione 16,l7-acetophenonide is obtained.

EXAMPLE 23 A -Pregnatriene-Ma,1 70:,21 Trial-3.12.20 T rione I 6,17-Acet0nide Following the procedure of Example 21 but substituting an equivalent amount of 9a-fiuoro-A -pregnadiene- 16a,l7a,2l-triol-3,12,20-trione 16,17-acetonide 2l-acetate for the aoetonide, A -pregnatriene-l6u,17::,2l-triol- 3,12,20-trione 16,17-acetonide is obtained.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of steroids of the general formula and the l,2-dehydro derivatives thereof, wherein R' is hydrogen, R" is fi-hydroxy and together R and R" is keto; R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid of less than ten carbon atoms; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic 1 1 heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic.

2. 9a-fiuoro-A -pregnene 12B,l6a,l7a,21 tetnol-3,20- dione 16,17-acetonide ZI-acetate.

3. 9a-fluoro A pregnene i6t1,l78,21 Moi-3,12,20- trione 16,17-acetonide 21-acetate.

4. A compound selected from the [group consisting of 9a-fluoro-A -pregnadiene 125,21 diol-3,20-dione, 9ozfluoro-A -pregnatriene-1219,21-diol-3,20-dione, and the 2l-esters of either with a hydrocarbon carboxylic acid of less than ten carbon atoms.

5. 9u-fluor0-A -pregnadiene 125,21 diol-3,20-dione ZI-acetate.

6. A compound selected from the group consisting of 9a-fluoro-A -pregnene l2{3,l6ot,17a,21 tetrol-3,20-dione, 9a fluoro-A -pregnadiene l2;3,16a,l7ot,21 tetrol-3,20- dione, and the 21-esters of either with a hydrocarbon carboxylic acid of less than ten carbon atoms.

8. A compound selected from the group consisting of 11,8,12fl-oxido-M-pregnene 16a,17a,21 triol-3,20-dione, 1lp,l2fl-oxid-o-A -pregnadiene 16a,17u,21 triol-3,20- dione, and the 2l-esters of either with a hydrocarbon carboxylic acid of less than ten carbon atoms.

9. l1B,1Zfl-oxido-M-pregnene-l6a,17:1,21-tri0l-3,2O-dione ZI-acetate.

10. A compound selected from the group consisting of steroids of the general formula CHnO R CHzOR e (it U and the 1,2-dehydro derivatives thereof, wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid of less than ten carbon atoms; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic and monocyclic heterocyclic lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of cycloalkyl and monocyclic heterocyclic.

13. A -Pregnadiene-16a,l7a,21-triol-3,12,20-trione 16,17-acetonide.

References Cited in the file of this patent UNITED STATES PATENTS Fried et al Sept. 19, 1961 OTHER REFERENCES 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE GENERAL FORMULA 